International audienceMany antibacterial agents, including the glycopeptides, are inactive against Gram-negative bacteria because of their inability to cross the outer membrane of these cells. Different chemical and technological approaches have been described to circumvent such limitation. In this study, we aimed to apply the strategy of fusogenic liposomes, up to now used to carry biological compounds and materials inside cells, to localise a glycopeptide antibiotic, vancomycin (VAN), to the periplasmic space, thus allowing it to exert its bactericidal activity. Small unilamellar liposome vesicles were prepared by an extrusion procedure (SUVETs) from a phospholipid-cholesterol hemisuccinate mixture known for its fusogenic properties with the eukaryotic cell membrane. VAN was loaded with high efficiency into these vesicles and in microbiological experiments in vitro was shown to be able to inhibit to a different extent the growth of wild and standard Gram-negative bacterial strains. Minimum inhibitory concentrations as low as 6mg/L were observed, for instance against clinical isolates of and . In comparison, neither the free antibiotic nor VAN-loaded 'classical' (non-fusogenic) liposomes showed any activity against the same bacteria. Scanning and transmission electron microscopy studies allowed confirmation that the produced SUVETs were able to adhere to and fuse with the external membrane of . According to preliminary experiments, this technological strategy can be proposed as a potentially successful way to enlarge the spectrum of activity of VAN
Bone metastases contribute to morbidity in patients with common cancers, and conventional therapy provides only palliation and can induce systemic side effects. The development of nanostructured delivery systems that combine carriers with bone-targeting molecules can potentially overcome the drawbacks presented by conventional approaches. We have recently developed biodegradable, biocompatible nanoparticles (NP) made of a conjugate between poly (D,L-lactide-co-glycolic) acid and alendronate, suitable for systemic administration, and directly targeting the site of tumor-induced osteolysis. Here, we loaded NP with doxorubicin (DXR), and analyzed the in vitro and in vivo activity of the drug encapsulated in the carrier system. After confirming the intracellular uptake of DXR-loaded NP, we evaluated the anti-tumor effects in a panel of human cell lines, representative for primary or metastatic bone tumors, and in an orthotopic mouse model of breast cancer bone metastases. In vitro, both free DXR and DXR-loaded NP, (58-580 ng/mL) determined a significant dose-dependent growth inhibition of all cell lines. Similarly, both DXR-loaded NP and free DXR reduced the incidence of metastases in mice. Unloaded NP were ineffective, although both DXR-loaded and unloaded NP significantly reduced the osteoclast number at the tumor site (P = 0.014, P = 0.040, respectively), possibly as a consequence of alendronate activity. In summary, NP may act effectively as a delivery system of anticancer drugs to the bone, and deserve further evaluation for the treatment of bone tumors.
A combined analysis of several high-resolution solid-state nuclear magnetic resonance experiments allowed the investigation of the structural and dynamic properties of the pure drugs and of the solid dispersions with the polymer, as well as of the degree of mixing between drug and polymer and of the chemical nature of their interaction. Such information could be related to the in vitro drug release profiles observed for the tested co-evaporates.
Contact with many different biological membranes goes along the destiny of a drug after its systemic administration. From the circulating macrophage cells to the vessel endothelium, to more complex absorption barriers, the interaction of a biomolecule with these membranes largely affects its rate and time of biodistribution in the body and at the target sites. Therefore, investigating the phenomena occurring on the cell membranes, as well as their different interaction with drugs in the physiological or pathological conditions, is important to exploit the molecular basis of many diseases and to identify new potential therapeutic strategies. Of course, the complexity of the structure and functions of biological and cell membranes, has pushed researchers toward the proposition and validation of simpler two- and three-dimensional membrane models, whose utility and drawbacks will be discussed. This review also describes the analytical methods used to look at the interactions among bioactive compounds with biological membrane models, with a particular accent on the calorimetric techniques. These studies can be considered as a powerful tool for medicinal chemistry and pharmaceutical technology, in the steps of designing new drugs and optimizing the activity and safety profile of compounds already used in the therapy.
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